Trained immunity vaccines: BCG as a tool to combat SARS-CoV-2 and future pandemics

Abstract

It was long assumed that immunological memory is exclusively a hallmark of adaptive immunity. However, it was recently discovered that the innate immune system has memory properties, termed ‘trained immunity’. Trained immunity is defined by long-term functional, metabolic, and epigenetic reprogramming of innate immune cells, resulting in an altered, often enhanced response to subsequent infection. Some existing vaccines can induce trained immunity, like the measles-mumps-rubella vaccine, yellow fever vaccine, and Bacillus Calmette-Guérin (BCG). Among these vaccines, trained immunity properties of the BCG vaccine are the most extensively studied. BCG induces trained immunity by inducing a shift in cellular metabolism towards glycolysis, and by inducing genetic alterations that promote the expression of pro-inflammatory cytokines in monocytes, macrophages, and natural killer (NK) cells. Moreover, BCG induces immune tolerance by promoting the activation of immunosuppressive T cells (Tregs). BCG might therefore offer protection against heterologous infections, while modulating its induced immune response and preventing hyperinflammation. Indeed, the BCG vaccine was shown to offer heterologous protection against infection by a wide range of bacteria, fungi, parasites, and viruses. Recent epidemiological studies implicate that BCG (re)vaccination also offers protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and disease morbidity and mortality. In the light of these findings, this thesis discusses the concept and mechanisms of trained immunity, the molecular mechanisms of BCG-induced trained immunity, and the potential of trained immunity vaccines as preventive measure or treatment during the current pandemic and those that are yet to come.